Background
Despite effective antiretroviral therapy (ART), people with HIV (PWH) experience higher morbidity and mortality rates than people without HIV due to ongoing inflammation from persistent HIV. Methamphetamine (MA) use disorder among PWH is linked to lower ART adherence, increased viral resistance and poorer clinical outcomes. We recently demonstrated that MA exposure during ART is associated with increased HIV transcription. Here, we performed single cell analyses to determine signaling pathways by which MA induces immune dysfunction, potentially driving viral transcription in PWH even during ART suppression.
Methods
Longitudinal inguinal lymph node (LN) samples were obtained from 10 ART-suppressed PWH with MA use disorder. Plasma MA concentrations were analyzed in relation to single cell gene (scRNA-seq) in LNs and protein (flow cytometry) expression from PBMCs. Linear regression models were used for comparisons.
Results
MA was associated with significantly higher expression of NLRP3 and IL-1β signaling genes from monocytes, dendritic cells (DCs), and neutrophils. Participants with high plasma concentrations of MA had significant upregulation of “TNF-α signaling via NF-κB” and “Inflammatory response” pathways in DCs, CD8 T cells, NKs, and granulocytes. B and plasma cells demonstrated significant upregulation of the “IFN alpha and gamma responses”. Higher plasma concentrations of MA was also associated to decreased expression of chromatin modifier genes in DCs, monocytes, and plasma cells, consistent with open chromatin state in these cell types. Flow cytometry data from CD4+ T cells demonstrated enhanced chromatin accessibility in participants with high MA concentrations.
Conclusions
Leveraging a unique cohort of PWH on ART with and without MA use disorder, we demonstrate that MA is associated with increased NLRP3 inflammasome activation, potentially driven by epigenetic changes to cell-specific subsets. Additionally, MA was associated with enhanced chromatin accessibility in CD4+ T cells, which, along with increased inflammatory signatures in all immune cell subsets, supports our prior findings that MA induces increased HIV residual transcription. Finally, we demonstrate that MA may induce humoral dysfunction, with clinical implications for decreased antibody responses in this population. These data highlight potential novel mechanisms by which MA may promote immune dysfunction in PWH, with implications for future strategies at reducing co-morbidities in this population.
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